Alzheimer's disease (AD) is a neurodegenerative disorder that currently has no cure and impacts millions of people worldwide. While the primary risk factor for AD is aging, new advances in genomic technology implicate inflammatory lipid signaling in microglia, the macrophages of the brain, as a driving force for cognitive decline in AD. However, despite these observations, the specific mechanisms by which microglia become inflamed and putatively exacerbate neurotoxicity within the AD brain are unknown. Thus, it is critically important to develop our understanding of the molecules that govern the impact of microglia on neuronal health and degeneration. Mounting evidence suggests a critical role for the Receptor for Advanced Glycation Endproducts (RAGE) in regulating microglia inflammation during AD. RAGE is an immunoglobulin-type, cell surface receptor that is expressed on numerous cell types in the CNS and periphery, including microglia and macrophages. It binds a diverse class of ligands, including: glycated proteins and lipids, S100/calgranulins, oligomeric A?, high mobility group box 1 (HMGB1), and phosphatidylserine (PS). This receptor is known to mediate potent inflammation in macrophages during chronic diseases, in which pathological ligands families are known to aberrantly accumulate. However, intriguingly, RAGE may also regulate homeostatic phagocytosis of apoptotic cells and protein debris. In order to probe the effects of RAGE in microglia during homeostasis and AD, we have generated novel (CX3CR1 CreERT2, RAGE flox/flox) mice in control and AD-like backgrounds. Thus, RAGE can be specifically deleted from microglia after tamoxifen induction in adult mice during diverse inflammatory contexts. Our overarching hypothesis is that RAGE signal transduction plays context- dependent dual and opposing roles in microglia. In low levels of RAGE ligands during homeostasis, RAGE contributes to adaptive microglia migration, phagocytosis and inflammation; in milieus of high levels of RAGE ligands, RAGE drives damaging inflammatory and oxidative stress in microglia, thereby triggering neuronal and synaptic dysfunction, and irreversible cognitive decline. Beyond the generation of novel models, we have developed a technique to isolate viable, highly pure, adult microglia in order to probe key microglia regulatory molecules and phagocytosis ex vivo. We will utlize these models and isolates to probe how RAGE alters microglia function during homeostasis (Aim 1) and distinct phases of AD progression (Aim 2). Finally, in order to further delineate the role of microglia RAGE, we will induce laser ablation injuries in the cortex of live mice and image control and RAGE-devoid YFP+ microglia migrating towards the site of injury (Aim 3). Through these experiments, we will elucidate the poorly understood mechanisms by which RAGE modulates microglia responses during homeostasis and neuroinflammatory stress. In doing so, this work will inform therapeutic strategies in the treatment of neuroinflammatory disease, specifically Alzheimer's disease.